| Mesenchymal stem cells (MSCs) have captured considerable scientific and public interest because of their multipotency, properties of immune regulatory and bioactive molecules secretion. Recently, increasing evidences have suggested the therapeutic potential of MSCs in various disorders. In this study, we mainly focus on the anti-fibrotic effect of mouse bone marrow MSCs (mBM-MSCs) in liver fibrosis, and the underlying cellular and molecular mechanisms.First, we demonstrated that mBM-MSCs could integrate into injured livers after transplantation with obvious anti-fibrotic effect, which probably through inhibiting hepatic stellate cells (HSCs) activation. Genome wide microarray analysis unexpectedly found that the mRNA level of Delta-like1(Dlkl) was dramatically elevated in CCl4-injured livers. Then we provided in vitro and in vivo evidences showing that Dlkl is a critical contributor to liver fibrosis through promoting HSCs activation during chronic liver injury. We found that upon liver injury, Dlkl was dramatically induced and initially expressed in hepatocytes, and then into the HSCs by paracrine manner. It leads to the activation of HSCs which is considered to be a pivotal event in liver fibrogenesis. Two forms (-50and-25kDa) of the Dlkl protein were detected by western blot analysis upon liver injury. The large soluble form (-50kDa) of Dlkl was shown to contribute to HSC activation in vitro. Then we are encouraged to find the Dlkl-promoted HSC activation and liver fibrosis can be depressed by transplantation of bone marrow mesenchymal stem cells (BM-MSCs). Furthermore, we demonstrated that fibroblast growth factor2(FGF2) was upregulated in BM-MSCs under injury stimulation and probably participated in the inhibition of Dlkl by BM-MSCs. Our findings provide a novel role of Dlkl in liver fibrosis leading to a better understanding of the molecular basis in fibrosis and cirrhosis, but also give insights into the cellular and molecular mechanisms of MSC biology in liver repair.
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